Detection of acute HIV infection (AHI), defined as the time between HIV acquisition and seroconversion, is of high public health importance. Studies indicate that transmissions during acute infection account for a disproportionate number of new HIV infections. Supporting the prevention importance of AHI detection, persons newly diagnosed with HIV dramatically reduce their risk behavior, and testing partners of AHI index cases results in a high percentage of newly diagnosed HIV cases. Attempts to detect AHI have mostly involved RNA-detection algorithms using pooled HIV antibody-negative specimens, commonly known as pooled nucleic acid amplification testing (NAAT). But pooling can be expensive, laborious, and operationally daunting. An alternative for AHI detection is to use antigen-antibody combination tests, so called fourth- generation immunoassays. Although such tests are not yet approved by the FDA in the United States, they are easy to perform, relatively inexpensive, and easily automated. However, there is a paucity of data available on the performance of fourth-generation assays relative to HIV RNA detection algorithms in the public health setting. Whether the potential increased efficiency of fourth-generation testing, and possible lower cost of such tests, compensate for missing infections otherwise detectable by NAAT pooling remains to be determined. In addition, the overall public health effect and cost-effectiveness of sexual partner and social network partner notification and testing in the setting of routine AHI screening requires further study. Therefore, as required in the RFA Screening Targeted Populations to Interrupt On-going Chains of Transmission with Enhanced Partner Notification the specific aims of this project are: 1. To evaluate the yield, cost-effectiveness, and feasibility of screening for AHI with a fourth-generation enzyme immunoassay (EIA) in high-risk/high-incidence settings compared to pooled NAAT. 2. To evaluate the yield, cost-effectiveness, and feasibility of enhanced partner notification/contact tracing techniques linked to AHI screening. The San Francisco Department of Public Health's (SFDPH) HIV Prevention Section is uniquely qualified to respond to this RFA. Expanding upon our well-coordinated HIV testing programs, we will collect and test 22,000 specimens for this project at sites with high HIV incidence, including among men who have sex with men (MSM) and MSM of color. All four proposed collaborating clinical sites have a long history collaborating with us on testing and partner notification interventions; three have experience with NAAT pooling. Our SFDPH Microbiology Lab has experience with fourth-generation EIA and a history of leadership, research and collaboration on cutting-edge public health initiatives. Finally, we have a twenty-five year history of successful collaboration with the Centers for Disease Control and Prevention, ensuring that scientific and operational goals will be met. PUBLIC HEALTH RELEVANCE: HIV testing improves health and reduces the chances that people will unknowingly transmit the virus. This project will determine if new types of HIV tests and testing strategies lead to earlier detection of HIV. Such tests may result in reduced HIV transmission, could reduce healthcare costs, and may improve public health among vulnerable populations at risk for HIV.